With aging, in both men and women, skin becomes thin, transparent, dry, and prone to uncontrolled growth of its superficial or epidermal layer. Sun exposure produces "photo-aging," which accelerates these changes and stimulates the development of premalignant, raised, roughened areas (actinic keratoses), and malignant tumors (squamous and basal cell carcinomas).
In aging skin, at the microscopic level, the outermost layer of cells, or "stratum corneum," shows diminished cellular cohesion. Furthermore, dry or cornified cells are shed more rapidly than in younger skin. In the deeper granular layer, the predominant cell type, called the keratinocyte, is known to have fewer intracellular keratohyalin granules and fewer subcellular organelles in older skin compared to younger skin.
The lipid-based "epidermal water barrier," which emanates from the granular layer, has been shown to have reduced complex lipid and ceramide content in aged skin when compared to younger skin. The characteristic subcellular organelle of the granular-layer keratinocyte is the "lamellar body" or "keratinosome," which is composed of phospholipids, ceramides, and free sterols. The lamellar bodies migrate to the periphery of the granular cell, where they fuse with the plasma membrane and expel their contents into the intercellular space. Once in the intercellular space, ceramides organize to form the intercellular cement, holding together the more superficial corneal cells and constituting the lipid barrier of the epidermis.
The precursors for biosynthesis of ceramides and specialized lipids include essential fatty acids and the action of subcellular organelles, called "microbodies" or "peroxisomes." Peroxisomes are enzyme-rich and are known to participate in the metabolism of long-chain fatty acids derived from the essential fatty acids.
Both exposure to ultraviolet light and aging are associated with diminished peroxisome numbers and enzymatic activity.
Basal cells form the deepest epidermal cell layer. With aging, they become shorter and less adherent to the dermal layer below. Their nuclei become irregularly shaped, supplying further evidence of disordered growth and differentiation of older, as compared to younger, skin.
Chronic sun exposure predominantly alters the dermis, where elastic fibers thicken, degrade, and degenerate in amorphous masses. Collagen is damaged due to proteolytic enzymes associated with ultraviolet-light-induced inflammation. As a result, wrinkles become deeper and permanent. Also within the dermis, sebaceous glands become larger and contain more cells, even though their production of sebum is less.
Therapy for skin-aging and photo-damage has been advocated to reduce occurrence of epidermal cancer with advancing age. Such therapies have included the use of sun-blocking chemicals, such as para-aminobenzoic acid and methoxy-cinnamate.
Most recently, topical therapy with active vitamin A derivatives, especially retinoic acid, have been shown to specifically stimulate tissue repair in the dermal layer and proliferation and thickening of the more superficial epidermal layers. Retinoid therapy results in a reduction of fine wrinkles, promotion of new collagen synthesis, and reduction of the occurrence of sun-induced basal cell carcinomas. However, retinoic acid therapy often causes dryness, redness, burning, peeling, and increased sun sensitivity of the skin. These side effects make retinoic acid therapy unacceptable to many individuals.
Microscopic study of retinoic acid-treated skin reveals altered keratin protein production, reduced cell-to-cell cohesion, changes in the composition of the lipid barrier of the granular layer, and cellular disorganization of the superficial stratum corneum. An increase in trans-epidermal water loss is seen with retinoid therapy which is similar to that observed in atopic dermatitis and congenital deficiency of the lipid barrier in ichthyosis.
Systemic therapy using oral retinoic acid has proved useful in preventing precancerous changes in the oral mucosa of the elderly ("leukoplakia") and in preventing the development of new tumors in individuals who have had previous squamous cell carcinomas of the head and neck. However, such systemic therapy with retinoids results in similar, or more severe, toxic reactions than those observed with topical use, including pseudo tumor cerebri, hepatitis, dry eye syndrome, hyperostosis, and hyperlipidemia.
A need exists for improved therapy to protect the skin from ultraviolet-light-associated damage and to reduce the toxicity of current retinoid therapy for various epithelial disorders. Preferably, such treatments would stimulate the natural biosynthesis of the epidermal lipid barrier in skin that is lost with aging and diminished as a result of retinoid use.